The field of the invention is melatonin and its receptors.
Melatonin, the principal hormone of the pineal gland, influences the timing of mammalian circadian rhythms and regulates the reproductive alterations that occur in response to changes in day length in seasonally breeding mammals (Reppert, S. M. and Weaver, D. T., Cell 83:1059-1062, 1995). In humans, melatonin administration has been shown to alleviate the symptoms of jet lag after air travel across several time zones. The hormone also has potent sedative effects in humans and may be a useful hypnotic agent.
Melatonin exerts these effects through specific guanine nucleotide binding protein,(G protein)-coupled receptors. A family of these G protein-coupled melatonin receptors has been cloned from Xenopus laevis, chicken and various mammals (U.S. applications Ser. Nos. 08/261,857, filed Jun. 17, 1994; 08/319,887, filed Oct. 7, 1994; and 08/466,103, filed Jun. 6, 1995; Ebisawa, T., et al. Proc. Natl. Acad. Sci. USA 91:6133-6137, 1994; Reppert, S. M. et al., Neuron 13:1177-1185, 1994; Reppert, S. M. et al. Proc. Natl. Acad. Sci. USA 92:8734-8738, 1995; Reppert, S. M. et al., Neuron 15:1003-1015, 1995). These cloned receptors exhibit affinity and pharmacological characteristics similar to each other and to endogenous receptors, as defined by the melatonin agonist 2- [.sup.125 I]-iodomelatonin (.sup.125,-Mel). Two mammalian melatonin receptor subtypes have been identified by molecular cloning studies. The mammalian receptor Mel.sub.1a is expressed in the hypothalamic suprachiasmatic nuclei (SCN) and hypophyseal pars tuberalis, which are presumed sites of the circadian and some of the reproductive actions of melatonin, respectively (Reppert, S. M. et al., Neuron 13:1177-1185, 1994). The mammalian Mel.sub.1b receptor is expressed in retina and brain and may mediate the reported effects of melatonin on retinal physiology in mammals (Reppert, S. M. et al. Proc. Natl. Acad. Sci. USA 92:8734-8738, 1995). A third receptor subtype, the Mel.sub.1c melatonin receptor, has been cloned from zebrafish, Xenopus, and chicken, but not from mammals (Reppert, S. M. et al., Neuron 15:1003-1015, 1995).